With the increase in complex biologics and combination devices that can be damaged or altered when exposed to extreme heat or radiation, terminal sterilization is not always an option.
Following aseptic manufacturing practices, every component of the final drug product, including the primary container, must be sterilized before processing in a controlled, sterile environment. Each component can be sterilized by either heat (dry or moist), radiation (gamma rays), filtration, or gas depending on its size and makeup.
What the FDA Says About Sterilization
The FDA current good manufacturing practice regulations (21 CFR 210 and 211) mention that “sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible.”
The guidance also offers a brief but important technical framework for terminal and aseptic sterilization processes:
“Terminal sterilization usually involves filling and sealing product containers under high-quality environmental conditions. Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful. In most cases, the product, container, and closure have low bioburden, but they are not sterile. The product in its final container is then subjected to a sterilization process such as heat or irradiation.”
“In an aseptic process, the drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. For example, glass containers are subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control. A terminally sterilized drug product, on the other hand, undergoes final sterilization in a sealed container, thus limiting the possibility of error.”
“Sterile drug manufacturers should have a keen awareness of the public health implications of distributing a nonsterile product. Poor CGMP conditions at a manufacturing facility can ultimately pose a life-threatening health risk to a patient.”
Best Practices for Aseptic Manufacturing
Glass and plastic containers — including bottles, syringes, vials, cartridges, and ampoules — are pre-sterilized before being introduced to the processing and packaging environment.
Glass containers typically undergo cleaning by WFI or high-purity water and sterilization by dry heat to remove any foreign objects and bacteria. Plastic containers are best suited for radiation, gas, or other non-heating methods to avoid container warping or melting.
Proper cleanroom design is critical to controlling and preventing contamination during aseptic manufacturing, with advanced HVAC systems and HEPA filters central to maintaining the purest air quality for the production of sterile products.
Traditionally, the flow of materials and personnel becomes increasingly stringent and sterile leading to the ISO 5 certified critical area. Today, restricted-access barrier systems (RABS) allow for far greater separation between product and people, further limiting the risk of contamination within a cleanroom.
Cleanrooms undergo continuous environment monitoring to ensure the air and all surfaces are regularly sampled and verified to be sterile.
Aseptic manufacturing equipment and processes range from manual hand-filled to semi-automated to fully automated. All equipment must be properly qualified for the intended use of the production area and be able to be sterilized.
Even in fully automated production environments, human interaction is necessary at some level. In addition to equipment and room design, it is critical to understand and control the level of human movement and involvement to limit the disruption and potential for contamination.
Any personnel involved in the aseptic manufacturing of drugs or devices should undergo extensive training in aseptic processes, cleanroom best practices, proper gowning and protection, personal hygiene, and specific operating procedures of the facility.
Consistent and ongoing education and retraining must be provided to all personnel.
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